Cerebrovascular diseases are common and frequently-occurring. They present a huge threat to human health due to their high fatality, disability, and resulting medical expenses; and patients affected tend to be increasingly younger. Ischemic brain injury is a common brain disease due to blood circulation disorder. Cerebral ischemia may cause energy metabolism dysfunction in local brain tissues, excitatory amino acid cytotoxic, excessive calcium influx, inflammatory cytokine release, free radical damage and other malignant cascade reactions, eventually leading to neuronal death. Currently, there are a variety of neuroprotective drugs for ischemic brain injury, including glutamate receptor antagonist, glutamate release inhibitors, antioxidants, calcium ion chelating agent, etc. Pathologically, however, ischemic brain injury involves a cascade process including multiple factors and channels; it is difficult for drugs with a single mechanism alone to effectively inhibit such a complex process. Hence unsatisfactory clinical treatment. Clinically, more effective drugs against ischemic brain injury are in great need.
Endocannabinoids system (ECS) acts as a protector by participating in regulating oxidative stress, trauma, ischemia and other pathological processes. ECS has become a new target for use of neuroprotective drugs. ECS is activated after ischemic injury; postsynaptic neurons are synthesized on demand and a large number of endocannabinoids anandamide (AEA) are released, acting on the presynaptic neurons cannabinoid receptors; and a variety of dysfunctions of damaged neurons are regulated through negative feedback to protect damaged nerve cells.
The N-stearoyl amino acid (e.g. N-stearoyl tyrosine, NsTyr) developed by our laboratory is a new AEA analogue, protecting nerve by intervening in ECS metabolic process. Previous studies have confirmed that NsTyr significantly intervened in vitro slices, neurons and a variety of PC12 cell injuries, improved the survival rate of hippocampal CA1 pyramidal cells for gerbil model in acute ischemia injury, and lessened the apoptosis of ischemic damaged neurons. However, N-stearoyl amino acid had a low solubility in water, and a low bioavailability as a neuroprotective drug.
Previous research of stearoyl amino acid and any salt as such focused on the nerve protective function of this compound. So far there has been no report of stearoyl amino acid or the medicinal salt thereof as a weight-loss drug. However, obesity is the leading cause to diabetes, cardiovascular diseases and nonalcoholic fatty liver diseases. What's worse, adult obesity rate has been sharply rising year by year worldwide, say, by 22% in 2013. Appetite suppressants sibutramine and rimonabant, though effective in weight loss, had to drop out of the market due to their side effects such as depression. FDA-approved weight-reducing drug Orlistat was reported to give a rare case of liver damage in phase IV clinical monitoring. Therefore, considering complex causes to obesity, desired weight loss drugs should have good security and be able to speed up hydrolysis against fat absorption and synthesis by regulating metabolic pathways within the body. By now, research of drugs for obesity has focused on discovering natural products that promote β-oxidation (the chief way of fat hydrolysis and catabolism). However, such natural products seldom reach desired effects when applied to fat animal models; at the same time, results of security assessment have also limited their development. Thus, developing new weight-reducing drugs with different mechanism meets huge societal demand, and theoretically is of great significance as well.